Evidence has shown that genetic susceptibility plays a significant role in breast cancer in women with African ancestry. Because of the high levels of genetic heterogeneity in individuals with African ancestry, common disease-common allele genetic causation model does not fit the breast cancer in women with African ancestry. Therefore, common SNP based GWAS and candidate gene studies to search for the risk alleles in breast cancer patients with African ancestry, so far, have not been as successful as we expected. Obviously, new genetic model and new approach are urgently needed. With the advance of genome technology and our understanding of rare variants in the development of human diseases, we hypothesize that genetic model for breast cancer in women with African ancestry is common disease-many rare alleles model. To test this hypothesis, in the current proposal we plan to take advantage of cutting-edge genome technology, whole exome sequencing analysis, to screen the entire coding regions (including both proteins and microRNAs) of selected AA individuals with enriched but unresolved genetic susceptibility of breast cancer, to prioritize a list of rare breast cancer risk allele. Rare (i.e., characterized by low frequency in general population) variants enriched in the functionally important exome regions of these extreme-phenotype patients might serve as candidate of genetic risk alleles with substantially large effect size. To test their contribution to breast cancer risk, we will perform a case control analysis to assess the associations between selected rare variants prioritized from whole exome sequencing and breast cancer risk. Our hypothesis is that women with African ancestry carrying the prioritized rare breast cancer risk alleles are at an increased risk of breast cancer. Because this research is nested within the Women's Circle of Health Study (WCHS), the objects can be addressed in a timely and cost effective manner. PUBLIC HEALTH RELEVANCE: The results from this study are expected to have an important positive impact, because the identified novel genetic risk alleles are highly likely to provide new clues to the genetic etiology of breast cancer in AA women, shed light on the genetic basis of racial disparity in breast cancer, as well as provide concrete evidence for the novel genetic model: the common disease-many rare alleles model of human diseases.